Preoperative Therapy with Trastuzumab

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Ultima Vez Modificado: 4 de noviembre del 2005

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Presenter: Eric P. Winer, MD
Presenter's Affiliation: Dana Farber Cancer Institute, Boston, MA
Type of Session: Scientific

Background

  • The NSABP B-18 trial randomized women with locally advanced breast cancers to receive either preoperative adriamycin and cyclophosphamide (AC), or the same regimen given post-operatively.
  • That trial demonstrated no statistically significant difference in either disease-free survival or overall survival between the two arms.
  • However, this trial did show that patients whose tumors responded to chemotherapy preoperatively (particularly if they had a pathologic complete response) had improved survival outcomes.
  • Using therapy preoperatively has a variety of advantages from a research perspective, including: providing early assessment of therapeutic activity, allowing for analysis of molecular changes due to therapy, and increasing the number of women who can undergo conservative surgery and radiation in lieu of mastectomy.
  • Trastuzumab is a monoclonal antibody which targets the HER-2 receptor.
  • Approximately 25-30% of breast cancers overexpress HER–2, and these tumors tend to grow faster and behave more aggressively than those that do not overproduce HER–2.

Materials and Methods

  • A study was performed which treated women with stage II/III breast cancer with preoperative paclitaxel and trastuzumab (for 12 weeks), followed by definitive surgery, and then AC chemotherapy.
  • About half of the patients in this trial were estrogen receptor positive (ER+).
  • The pathologic complete response rate (PCR) in this study was 18%.
  • A similar study utilized vinorelbine with trastuzumab preoperatively, and found a PCR rate of 19%, with a clinical response rate of 88%.
  • 80% of these patients had no change in their HER-2 status.
  • No trastuzumab study has demonstrated a difference in response rates related to ER/PR status, which is in contrast to preoperative chemotherapy trials, which have shown that ER- patients are more likely to respond to chemotherapy.
  • Preliminary findings from gene profiling studies suggest that tumors that overexpress HER-2 are quite heterogeneous.
  • Identifying the underlying differences in these tumors may explain their differential responses to therapy and may also identify new targets for therapy.
  • An ongoing phase II trial at Harvard is randomizing patients to either vinorelbine/trastuzumab or carboplatin/docetaxel/trastuzumab after treating every patient up front with a dose of trastuzumab.

Results

  • At MD Andersen, a preoperative trial planned to randomize patients to paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), or to the same regimen given concurrently with trastuzumab.
  • The study was stopped by the data safety monitoring board after 34 patients had gone to surgery because of the substantial difference in pathologic complete response rates seen in the trastuzumab arm (65% vs 25%, p=0.016).
  • The results of this study are not in keeping with other studies of preoperative trastuzumab, and many people have speculated as to why.
  • Hypotheses for this extremely high PCR rate include:
    • this was a chance phenomenon
    • the patients were more favorable in this study (only stage I/II disease)
    • the trastuzumab was given over a prolonged course (24 weeks as opposed to 12 weeks)
    • an anthracycline was included in the regimen
    • the trastuzumab was given concurrently with the anthracycline
  • ER status did not correlate with PCR rate in this study.
  • There was no excess cardiac toxicity reported in the trastuzumab arm, and no unexpected toxicities were seen.
  • Based on this study, ACOSOG created a large trial to verify these findings, with PCR as the primary endpoint.
  • The Baylor group has experimented with preoperative trastuzumab as monotherapy, and have reported that a low Ki-67 (a marker of how quickly the tumor is proliferating) status predicted for response to trastuzumab.

Author's Conclusions

  • Significant data now exist demonstrating a benefit to giving adjuvant trastuzumab for 1 year following surgery.
  • Preoperative trastuzumab appears feasible with limited acute toxicities.
  • This strategy produces relatively high PCR rates.
  • Preoperative therapy is a promising therapeutic approach deserving of further research.
  • It is reasonable to consider giving preoperative trastuzumab off-study, especially to patients with large tumors who would like to undergo breast conservation.
  • Treatment with trastuzumab is equally effective when given either preoperatively or postoperatively.
  • One should be cautious about using trastuzumab concurrently with an anthracycline until there is better safety data available.
  • Based on adjuvant data, trastuzumab should be continued for one year.

Clinical/Scientific Implications

Dr. Winer presented a clear and concise review of the efficacy of trastuzumab given preoperatively for women with locally advanced breast cancers.  Dr. Winer’s conclusions are valid, and trastuzumab appears to improve pathologic complete response rates when given with systemic chemotherapy.  Tumor response rates have been demonstrated to be an effective surrogate endpoint for breast cancer patients, but it would still be nice to have actual survival outcome data for this drug.  Eventually, preoperative trastuzumab may very well prove to be an agent that improves survival.  The MD Andersen study has an amazingly high PCR rate, and this finding has not yet been validated.  Dr. Winer is correct in suggesting caution regarding the use of trastuzumab concurrently with an anthracycline before toxicity data has matured.  However, it may be prudent to consider studying a long course of preoperative trastuzumab (24 weeks), as was done in the MD Andersen study.  This is an exciting new development in the field of breast oncology, and the scientists and physicians responsible for this drug should be commended for their work.

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